The overall aim of this proposal was to examine the mechanisms of impaired natural cytotoxicity mediated by natural killer (NK) cells in human diseases. A group of patients with colon and any other cancers was examined. The depressed NK activity was not related to the stage of the disease. The response of NK function to interferon (INF) was reduced in some of these patients. In addition, 40% of the patients had suppressive serum factors which were not either anti-lymphocyte antibodies or immune complexes. Some patients with systemic lupus erythematosus (SLE) also have a suppression of NK activity. The impaired NK activity in SLE did not appear to be related to a cell-mediated suppressive mechanism or to a depletion of effector cells. However, the release of natural killer cytotoxic factor (NKCF) was abnormal. The defective response of the NK cell to INF in SLE patients was found to be secondary, in part, to the presence of inhibitory serum factors and preactivation by INF. The inhibiting serum factors suppress NK function without evidence of lymphocyte cell death or inhibition of NK effector cell binding to tumor targets. The production of interleukin-2 (IL-2) and INF was normal in SLE patients so that the synthesis of these factors is not a major pathologic factor in the development of SLE. One aspect of OKM1+ cells was sheep erythrocyte positive (E+) while the others were not (E-). The OKM1+ E+ cells mediated more NK activity on a per cell basis than E-\OKM+ cells. In addition, the regulation of NK activity by neuropeptides (beta-endorphin and enkephalines) was examined. These neuropeptides increased the numbers of effector cell:tumor conjugates and the number of active killer cells among target-binding cells. Other studies have focused on suppressive cells associated with human immunodeficiency. We found, for example, that the major suppressor cell present in human cord blood is an OKT8+/lymphocyte. During the last year significant progress has been made concerning the regulation of NK activity in human diseases. The impairment of peripheral NK activity is not related to a decrease in the potential number of NK effector cells which bind target cells, but to an inhibition of activity due to multiple factors such as anti-lymphoid cell antibodies, immune aggregates, and other unidentified materials. In certain diseases, it appears that a relative refractoriness to enhancing factors such as INF may contribute to impaired NK activity. An important observation that neuropeptides such as beta-endorphin can influence NK activity was made. New observations concerning another type of cytotoxic cell, the so-called LAK cell, and its regulation by PG and factors produced by tumor cells may lead to important new data regarding the control of the LAK cell system and its relevance to the development of human cancers. (IS)